Quantitative reactivity studies substituents

Reactions involving monocyclic six-membered heteroaromatic rings have not been studied sufficiently extensively to allow a quantitative treatment of substituent effects. However, comparison with aza-naphthalene reactivities indicates that aza- and polyaza-benzene systems must also be highly selective. 

Methods have been presented, with examples, for obtaining quantitative structure-property relationships for alternating conjugated and cross-conjugated dienes and polyenes, and for adjacent dienes and polyenes. The examples include chemical reactivities, chemical properties and physical properties. A method of estimating electrical effect substituent constants for dienyl and polyenyl substituents has been described. The nature of these substituents has been discussed, but unfortunately the discussion is very largely based on estimated values. A full understanding of structural effects on dienyl and polyenyl systems awaits much further experimental study. It would be particularly useful to have more chemical reactivity studies on their substituent effects, and it would be especially helpful if chemical reactivity studies on the transmission of electrical effects in adjacent multiply doubly bonded systems were available. Only further experimental work will show how valid our estimates and predictions are. 

The correlation results for the bromination of diarylethylenes [31(X,Y)] summarized in Table 14 also involve the same serious problem. The p value increases significantly as the fixed substituent Y becomes more EW. This behaviour is indeed what is expected for the quantitative reactivity-selectivity relationship. However, in Table 14, the range of variable substituents X involved in the correlation of the respective Y sets is evidently different from set to set. The correlation for the Y = p-MeO set giving p = -2.3 should be referred to as the correlation for the T-conformation where X is more EW than Y, correlations for Y = p-Me, H and p-Br sets giving p = -3.6 may be referred to the E-conformation, and those for Y = m-Hal, especially P-NO2, refer without doubts to the P-conformation. The variation of p value cited in Table 14 demonstrates nothing other than the dependence of the selectivity p upon the propeller conformation of the diaryl carbocations. While there is no doubt regarding the importance of RSR in the mechanistic studies, these results lead to the conclusion that the RSR, or most of the non-additivity behaviour of a,a-diarylcarbocation systems which have been cited as best examples of quantitative RSR, may indeed be only an artifact. 

The most notable studies are those of Ingold, on the orienting and activating properties of substituents in the benzene nucleus, and of Dewar on the reactivities of an extensive series of polynuclear aromatic and related compounds ( 5.3.2). The former work was seminal in the foundation of the qualitative electronic theory of the relationship between structure and reactivity, and the latter is the most celebrated example of the more quantitative approaches to the same relationship ( 7.2.3). Both of the series of investigations employed the competitive method, and were not concerned with the kinetics of reaction. 

A quantitative study has been made on the effect of a methyl group in the 2-position of five-membered heteroaromatic compounds on the reactivity of position 5 in the formylation and trifluoroacetylation reaction. The order of sensitivity to the activating effect of the substituent is furan > tellurophene >selenophene = thiophene (77AHC(2l)ll9). 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

The propensity of S-S dications to undergo dealkylation was found to decrease in the order of methyl > ethyl > benzyl. This order of reactivity parallels the increase in the stability of the corresponding carbocations.94 Dealkylation of dication 77 affords thiosulfonium salt 78 in quantitative yield.95 Kinetic studies suggest SN1 mechanism of dealkylation. In addition, reaction of sulfoxide 79 with a substituent chiral at the a-carbon results in racemic amide 80 after hydrolysis. 

By comparison with the extensive kinetic results available for the quatemization of six-membered rings, especially where substituent effects on reactivity are concerned, few quantitative studies have involved five-membered heterocyclic rings. These are considered next. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

Novel techniques for the study of fast reactions were employed to study the bromination of AT.AT-dimethylaniline and its derivatives by Bell and Ramsden (1958). The second-order rate constant for the bromination of N,AT-dimethylaniline in acid solution was approximately 109 1. mole-1 sec-1. An estimate of the rate of bromination relative to the rate of substitution of benzene indicates that the methylated aniline is 1019 times more reactive (Robertson et al., 1953). The large influence of the p-dimethylamino substituent has discouraged extended quantitative study. Nevertheless, Eabom and his associates (Eabom, 1956 Eaborn and Pande, 1961a Eabom and Waters, 1960) assessed the influence of the group in several displacement reactions. Eaborn points out, however, that the resulting partial rate factors are only approximate. 

The introduction of a second aza group into the 5-membered rings reduces further the susceptibility to electrophilic attack. Triazoles,212, 213 oxadiazoles214, 215 and thiadiazoles216-218 are practically completely resistant to electrophilic substitution unless powerful electron-releasing substituents are present. No quantitative studies on the reactivities of these rings have been made. 

The fact that none of these reports has emphasized the physical aspects of electrophilic substitution in the series reflects the paucity of quantitative studies, and the low reactivity of these compounds in the presence of electrophiles. Few kinetic studies have been reported and the regio-chemical effects of substituents have seldom been quoted in quantitative form. The present chapter brings together those quantitative results that are available, and collates data on substituent effects. One worthwhile field of study would appear to be the application to the azines of Taylor s method involving thermolysis of esters [75JCS(P2)277, 75JCS(P2) 1783]. 

Hydrogen abstraction by triplet carbonyl compounds has been the most widely studied excited state reaction in terms of structural variations in reactants. Consequently, the most detailed structure-reactivity relationships in photochemistry have been developed for hydrogen abstraction. These correlations derive from studies of both bimolecular reaction and intramolecular reactions. The effects of C—H bond strength and the inductive and steric effects of substituents have been analyzed. The only really quantitative comparisons between singlets and triplets and between n,n and 71,71 states have been provided by studies of photoinduced hydrogen abstractions. 

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